Transplantation of organs and tissues is an important aspect of treating end-stage organ failure and replacing damaged tissue. However, despite advances in this field, rejection continues to be a major obstacle to successful transplantation.
The antigenic differences between individual members of the same species are referred to as "alloantigens." When alloantigens are involved in rejection of allogeneic tissue grafts they are referred to as "histocompatibility antigens." The terms "major histocompatibility antigens" and "major histocompatibility complex" (MHC) refer to the products of a single closely linked region of genes.
The MHC gene products are displayed on cell surfaces and are an important barrier to successful allotransplantation. In humans, the MHC is, by international agreement, referred to as "HLA." (Carpenter, C. B., in Harrison's Principles of Internal Medicine, ed. E. Braunwald et al., (McGraw-Hill, New York, 1987, page 337.) The individual letters in this abbreviation have a variety of meanings, including "Human Leukocyte (or Lymphocyte) Antigen" and "Histocompatibility Locus Antigen."
Graft rejection is the consequence of the host immune response to histocompatibility antigens expressed by the graft tissue. Allografts generally survive for a period of days to weeks, but may subsequently become inflamed and infiltrated with lymphocytes and monocytes. The graft tissue eventually becomes necrotic, and in the case of skin transplant, is sloughed from the skin. However, in the case of a vital organ such as the heart, the sequelae to tissue rejection can be fatal to the recipient.
In humans, cardiac transplants are closely monitored for signs of graft rejection. Commonly, this entails the performance of endomyocardial biopsies on cardiac transplant recipients weekly for the first 8 weeks after transplant, every other week for the next 8 weeks, monthly for the next year, and every 3-4 months for the remainder of the patient's life (Ahmed-Ansari, A. et al., Transplantation 45:972-978 (1988)).
The biopsied tissue is studied histologically for indicia of tissue rejection. A grade of rejection is determined on the basis of the degree of infiltration by leukocytes and cell necrosis. (Ahmed-Ansari et al., supra). It is believed that some of the infiltrating lymphocytes function as killer cells and attack graft tissues. Infiltrating lymphocytes produce lymphokines such as interferons, and interferon gamma is a potent stimulator of MHC induction. Expression of MHC antigens by the graft tissue is enhanced by the lymphokines, and graft cells become more sensitive to killer cells (Lindahl, P. et al., Proc. Nat. Acad. Sci. 73:1284-1287 (1976); Heron, I. et al., Proc. Nat. Acad. Sci. 75:6215-6219 (1978)).
In view of the discomfort and risks associated with repeated biopsy, there is a need for a non-invasive method of detecting early stages of allograft rejection.